Synthetic cannabinoid CUMYL-4CN-BINACA induces oxidative stress, ER stress, and apoptosis in brain and testicular tissues of male albino rats

Synthetic cannabinoids (SCs), including CUMYL-4CN-BINACA, are potent psychoactive compounds increasingly associated with severe neurotoxicity and systemic damage. Despite its prevalence in forensic toxicology, the molecular mechanisms underlying its effects on the brain and reproductive systems remain elusive. The current study investigated the impact of subacute exposure to CUMYL-4CN-BINACA at doses of 0.25, 0.5, and 1 mg/kg/day, administered intraperitoneally for 14 days. The focus was on assessing oxidative stress, endoplasmic reticulum (ER) stress, inflammation, and apoptosis in the brain and testis of male albino rats. Biochemical analyses revealed a significant dose-dependent increase in malondialdehyde (MDA) and reduction in glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), indicating redox imbalance. Gene expression profiling showed downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its targets HO-1 and NQO1, coupled with upregulation of ER stress markers (ATF6, PERK, IRE1). Apoptotic activation was evident by increased Bax and caspase-3, and decreased Bcl-2 levels. Neuroinflammatory mediators, including TNF-α, IL-6, IL-1β, and NF-κB, were significantly elevated in the brain but exhibited dose-variable responses in the testis. Notably, cannabinoid receptor 1 and 2 (CBR1 and CBR2) expression increased in both tissues, suggesting receptor-mediated toxicity. These findings indicate the multi-organ toxicity of CUMYL-4CN-BINACA and implicate oxidative stress, ER dysfunction, and inflammation as key mediators. Given the widespread use of SCs, this study highlights the need for increased awareness and a deeper understanding of their neuroimmune and reproductive hazards.